Abstract
Balamuthia mandrillaris and Naegleria fowleri are opportunistic protozoan pathogens capable of producing infection of the central nervous system with more than 95% mortality rate. Previously, we have synthesized several compounds with antiamoebic properties; however, synthesis of compounds that are analogues of clinically used drugs is a highly desirable approach that can lead to effective drug development against these devastating infections. In this regard, compounds belonging to the azole class possess wide range of antimicrobial properties and used clinically. In this study, six novel benzimidazole, indazole, and tetrazole derivatives were synthesized and tested against brain-eating amoebae. These compounds were tested for their amoebicidal and static properties against N. fowleri and B. mandrillaris. Furthermore, the compounds were conjugated with silver nanoparticles and characterized. The synthetic heterocyclic compounds showed up to 72% and 65% amoebicidal activities against N. fowleri and B. mandrillaris respectively, while expressing up to 75% and 70% amoebistatic activities, respectively. Following conjugation with silver nanoparticles, amoebicidal activities of the drugs increased by up to 46 and 36% versus B. mandrillaris and N. fowleri. Minimal effects were observed when the compounds were evaluated against human cells using cytotoxicity assays. In summary, azole compounds exhibited potent activity against N. fowleri and B. mandrillaris. Moreover, conjugation of the azole compounds with silver nanoparticles further augmented the capabilities of the compounds against amoebae.
Highlights
Balamuthia mandrillaris and Naegleria fowleri are free-living amoebae known to instigate granulomatous amoebic encephalitis (GAE) and primary amoebic meningoencephalitis (PAM), respectively, which are infections of the central nervous system (CNS) [1,2]
Amoebicidal assays were implemented to establish the ability of conjugation of azole compounds with silver nanoparticles to enhance the amoebicidal activities of the compounds
The synthesis of compounds that are analogues of clinically used drugs is a highly desirable approach that can lead to effective drug development
Summary
Balamuthia mandrillaris and Naegleria fowleri are free-living amoebae known to instigate granulomatous amoebic encephalitis (GAE) and primary amoebic meningoencephalitis (PAM), respectively, which are infections of the central nervous system (CNS) [1,2]. Benzimidazoles are heterocyclic compounds that exhibit a wide range of biological properties [6]. The derivatives of indazoles exhibits anticancer, antibacterial, anti-inflammatory, antiviral, antioxidants, antidiabetic, antituberculosis, antispermetogenic, and antiproliferative activities [14]. It has been shown that indazoles possess anti-protozoan activity against Trichomonas vaginalis and Trypanosoma cruzi [15]. It has been reported that tetrazoles possess antibacterial activities against Pseudomonas aeruginosa, Bacillus pumilis, Bacillus subtilis, Escherichia coli, and Staphylococcus aureus [22,23]. Considering that benzimidazole, indazole, and tetrazole derivatives display an extensive range of biological activities, we synthesized and characterized novel azole compounds (Table 1) and tested them against N. fowleri and B. mandrillaris. Azole compounds exhibited potent antiamoebic activity against N. fowleri and B. mandrillaris and conjugation of the azole compounds with silver nanoparticles further augmented capabilities of the compounds against these amoebae.
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